1. Field of the Invention
The present invention relates to drug delivery and formulation and specifically to particles of lipidated glycosaminoglycans encapsulating water insoluble or poorly water soluble drugs and their use in diagnosing and treating pathological conditions.
2. Description of the Related Art
Glycosaminoglycans, or mucopolysaccharides, along with collagen, are the chief structural elements of all connective tissues. Glycosaminoglycans, or gags, are large complexes of polysaccharide chains associated with a small amount of protein. These compounds have the ability to bind large amounts of water, thereby producing a gel-like matrix that forms the body's connective tissues. Gags are long chains composed of repeating disaccharide units (aminosugar-acidic sugar repeating units). The aminosugar is typically glucosamine or galactosamine. The aminosugar can also be sulfated. The acidic sugar may be D-glucuronic acid or L-iduronic acid. In vivo, gags other than hyaluronic acid are covalently bound to a protein, forming proteoglycan monomers. The polysaccharide chains are elongated by the sequential addition of acidic sugars and aminosugars.
Among the most common gags are hyaluronic acid, keratan sulfate, chondroitin sulfate, heparin sulfate, and dermatin sulfate. Gags may be chemically modified to contain more sulfur groups than in their initially extracted form. In addition, gags may be partially or completely synthesized and may be of either plant or animal origin.
Hyaluronic acid is a naturally occurring member of the glycosaminoglycan family which is present in particularly high concentration in the cartilage and synovial fluid of articular joints, as well as in vitreous humor, in blood vessel walls, and umbilical cord and other connective tissues. Hyaluronic acid can be in a free form, such as in synovial fluid, and in an attached form, such as an extracellular matrix component. This polysaccharide consists of alternating N-acetyl-D-glucosamine and D-glucuronic acid residues joined by alternating β-1,3-glucuronidic and β-1,4-glucosaminidic bonds. In water, hyaluronic acid dissolves to form a highly viscous fluid. The molecular weight of hyaluronic acid isolated from natural sources generally falls within the range of 5×104 up to 107 daltons. Hyaluronic acid has a high affinity for the extracellular matrix and to a variety of tumors, including those of the breast, brain, lung, skin, and other organs and tissues.
Drug delivery systems are used for maintaining a constant blood level of a drug over a long period of time by administering a drug into the body, or for maintaining an optimal concentration of a drug in a specific target organ by systemic or local administration, and over a prolonged period of time. For instance, chemically modified hyaluronic acid can be used for controlled release drug delivery. Balazs et al, in U.S. Pat. No. 4,582,865, reported that cross-linked gels of hyaluronic acid can slow down the release of a low molecular weight substance dispersed therein but not covalently attached to the gel macromolecular matrix. Other forms of pharmaceutical preparations/formulations are used as drug delivery systems, including the use of a thin membrane of a polymer or the use of a liposome as a carrier for a drug.
There are two basic classes of drug carriers: particulate systems, such as cells, microspheres, viral envelopes, and liposomes; and non-particulate systems, which are usually soluble systems, consisting of macromolecules such as proteins or synthetic polymers.
The majority of drug dosage forms available in the clinic (over 99%) are however formulations of free drugs. Nevertheless, microscopic and submicroscopic particulate carriers, performing as drug delivery systems, are used to improve clinical outcomes compared to treatment with free drug. Enclosure within a carrier protects the drug from the biological environment, reducing the risk of degradation and inactivation. Encapsulation also protects the biological environment from indiscriminate distribution of free drug, reducing the risk of toxicity and adverse side effects. Carrier mediation reduces pre-mature drug clearance and ensures a constant blood level of drug and/or an optimal concentration of drug in target organs over a prolonged period of time by systemic or by local administration. Particulate carriers perform as sustained-release or controlled-release drug depots, thereby contributing to improved drug efficacy and allowing reduction in dosing frequency.
Despite the advantages offered, there are some difficulties associated with using drug encapsulating biopolymers. For example, biopolymers structured as microparticulates or nanoparticulates have limited targeting abilities, limited retention and stability in circulation, potential toxicity upon chronic administration, and the inability to extravasate. Numerous attempts have been made to bind different recognizing substances, including antibodies, glycoproteins, and lectins, to particulate systems, such as liposomes, microspheres, and others, in order to confer upon them some measure of targeting. Although bonding of these recognizing agents to the particulate system has met with success, the resulting modified particulate systems did not perform as hoped, particularly in vivo.
Other difficulties have also arisen when using such recognizing substances. For example, antibodies can be patient-specific, and thereby add cost to the drug therapy. Additionally, not all binding between recognizing substrate and carrier is covalent. Covalent bonding is essential, as non-covalent binding might result in dissociation of the recognizing substances from the particulate system at the site of administration, due to competition between the particulate system and the recognition counterparts to the target site for the recognizing substance. Upon such dissociation, the administered modified particulate system can revert to a regular particulate system, thereby defeating the purpose of administration of the modified particulate system.
When it comes to drugs that have poor aqueous solubility (to be referred henceforth as poorly water-soluble and water insoluble drugs), there is further deficiencies in treatment with the free drug. In order to generate a dosage form that will allow treatment at all, it is necessary to formulate the water insoluble or poorly water soluble drug in a vehicle that will be hydrophobic enough to solubilize the drug, yet be hydrophilic enough to accommodate administration into an aqueous medium. These vehicles are usually detergent-like, such as the 1:1 blend of Cremophor EL (polyethoxylated caster oil) and ethanol used for paclitaxel. The drawback is that these vehicles and other similar detergent-based vehicles are highly toxic and cause hypersensitivity reaction and release of histamines in patients.
U.S. Pat. No. 5,733,892 to Sakurai et al. discloses lipidated glycosaminoglycan molecules which are soluble in aqueous solution. WO 03/015755 discloses a similar system of lipidated glycosaminoglycan particles which form suspensions of particles in an aqueous phase. The present invention is an improvement of the lipidated glycosaminoglycan particles of WO 03/015755 as none of the currently available delivery technologies provide a satisfactory solution to the problems associated with targeted delivery of water insoluble and poorly water soluble drugs.
Citation of any document herein is not intended as an admission that such document is pertinent prior art, or considered material to the patentability of any claim of the present application. Any statement as to content or a date of any document is based on the information available to applicant at the time of filing and does not constitute an admission as to the correctness of such a statement.